The current state-of-the-art in genomics and genetics involves the use of these technologies to understand the genetic basis of disease. Although these types of studies have proven scientifically interesting and have significantly furthered our understanding of the genetic and biochemical basis of inherited illness, they have had little effect on the economic commercial development of mass-market drugs. As a result, the promise of genomics as an enabling technology in the development of new and improved clinical compounds has remained unrealized.
This difficulty derives from the fundamental fact that disease genes and drug target genes belong to entirely different classes of genomic targets with little intersection between the two groups. For example, it is known that a loss-of-function (LOF) mutation in a gene, identified as BRCA1, increases the risk for breast cancer. While this knowledge is of great importance to cancer biology, it does little to accelerate the development of new drugs to treat breast cancer. This is because most drugs are antagonists. That is, the drugs cause a loss-of, or interference, with protein function, so that any drug that inhibits the function of the BRCA1 gene or its associated protein is more likely to increase the risk for breast cancer than reduce it. Gene therapy or protein replacement therapy may offer a path forward, but the prevailing paradigm is that a disease gene is a handle onto a biochemical pathway that will ultimately lead to a new drug target. This leap of faith, despite significant historical investment, has resulted in the development of few, if any, new pharmaceutical compounds.
For this very reason, recent efforts to use genomics as a tool for drug development have had disappointing results, primarily due to a focus on disease gene identification as an essential first step in the drug development process. A dramatic, but by no means unique example of this is the cloning and characterization of the mutation in the gene responsible for cystic fibrosis. Cloning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene was a watershed in human genetics, as it was the first time that a gene for a genetic illness was cloned entirely using positional cloning (genomic-genetic) technologies. Collins, F. S., Drumm, M. L., Cole, J. L., Lockwood, W. K., Vande Woude, G. F., and Iannuzzi, M. C., Science 235(4792):1046-9 (1987).
When the discovery of the gene was reported in 1989, a treatment for the disease was believed to lie just around the corner. Unfortunately, many researchers underestimated the complexity of deciphering the CFTR biochemical pathway, and of developing new drugs or gene therapies to treat the most common inherited deficiency in the CFTR gene. In fact, in more than a decade since the discovery of CFTR, only two major new drugs to treat cystic fibrosis have been developed. Neither of these drugs, Tobramycin and Pulmozyme, were developed by relying on specific knowledge of the cystic fibrosis-causing genetic defect. Although genomics has been a powerful tool for understanding the cause of many simple, inherited human illnesses, it has been less effective at identifying and validating drug targets for the pharmaceutical industry.
The focus on the disease process and the identification of genes associated with disease have led to unsatisfactory results. Present efforts have focused on segments of the population afflicted by a particular disease. Therefore, it can be appreciated that there is a significant need for techniques that rely on the analysis of phenotypes other than the disease phenotype, thereby enabling the identification of validated drug targets and the development of new diagnostics and vaccines. The present invention provides this and other advantages as will be apparent from the following detailed description and accompanying figures.